Aryloxyalkyl keto-esters

ABSTRACT

Aryloxyalkyl keto-esters, useful as anti-viral agents, are prepared from an aryloxyalkyl halide and an alkali metal enolate salt of a keto-ester.

This application is a divisional of copending application Ser. No.725,160, filed Sept. 21, 1976, now U.S. Pat. No. 4,133,959, which is inturn a continuation-in-part of copending application Serial No. 576,311filed May 12, 1975, now U.S. Pat. No. 4,031,246, which is in turn acontinuation-in-part of application Ser. No. 381,406, filed July 23,1973, now U.S. Pat. No. 3,933,837.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to aryloxyalkyl diketone and keto-esters, to thepreparation thereof and to compositions and methods for the use thereofas anti-viral agents.

(B) Description of the Prior Art

Chodnekar et al. U.S. Patent 3,686,222 discloses ethers of the formulaR-O-Ar wherein Ar is methylenedioxyphenyl and R is an aliphatichydrocarbon radical or an epoxide derivative thereof, useful aspesticides having juvenile hormone activity.

Erickson U.S. Pat. No. 3,787,443 discloses ethers of the formula R-O-Arwherein Ar is methylenedioxyphenyl or other substituted phenyl groups,and R is an aliphatic hydrocarbon radical or an epoxide or episulfidederivative thereof, useful as pesticides having juvenile hormoneactivity.

Collins U.S. Pat. No. 3,829,475 discloses diketones and keto-esters ofthe formula RR'CH-Alk-Ar wherein R is acyl, R' is acyl or carboalkoxy,Alk is an alkylene bridge and Ar is phenyl or substituted phenyl, usefulas pesticidal and antiviral agents; no aryl ethers are disclosed.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention relates to compounds ofthe formula RR'CH-Alk-O-Ar wherein R is alkanoyl or carbalkoxy, R' isalkanoyl, Alk is alkylene and Ar is phenyl or substituted phenyl, usefulas anti-viral agents.

In further composition of matter aspects, the invention relates tointermediates of the formula RR'CH-Alk-X where Alk is alkylene and X isBr or I; and intermediates of the formula 2-Cl-4-CH₃ O-C₆ H₃ -O-Alk'-Clwhere Alk' is alkylene interrupted by an oxygen atom.

In a further composition of matter aspect, the invention relates to acomposition for combatting viruses which comprises an antivirallyeffective amount of a compound of the formula RR'CH-Alk-O-Ar inadmixture with a suitable carrier or diluent.

In a process aspect, the invention relates to a process for obtainingthe compounds of the invention by treating a compound of the formulaX-Alk-O-Ar, where X is bromine or iodine, with a compound of the formulaRR'CH-M+ where M+ is an alkali metal cation; or, conversely, reacting acompound of the formula RR'CH-Alk-X with a compound of the formulaArO-M+.

In a further process aspect, the invention relates to a method forcombatting viruses which comprises contacting the locus of said viruseswith an anti-virally effective amount of a compound of the formulaRR'CH-Alk-OAr in admixture with a suitable carrier or diluent.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

The compounds of the invention are of the structural formula ##STR1##wherein: Alk is alkylene of 3 to 10 carbon atoms optionally interruptedby an oxygen atom separated by at least two carbon atoms from theterminal bonds of Alk;

R is alkanoyl of 2 to 6 carbon atoms;

R' is alkanoyl of 2 to 6 carbon atoms or carboalkoxy of 2 to 6 carbonatoms;

and Ar is phenyl or phenyl substituted by one to three substituentsselected from the group consisting of alkyl of 1 to 4 carbon atoms,alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms,alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxy of 2 to 4 carbonatoms, halogen, cyano, nitro, acetyl, sulfo, aminosulfonyl,trifluoromethyl, trifluoromethoxy, hydroxy, benzyloxy, carboxy,carboalkoxy of 2 to 4 carbon atoms, acyloxy of 1 to 10 carbon atoms,dialkylamino where alkyl has from 1 to 4 carbon atoms, anddialkylaminoalkoxy where alkyl has from 1 to 4 carbon atoms and alkoxyhas from 2 to 4 carbon atoms.

Also within the scope of the invention are pharmaceutically acceptableheavy metal chelates of the foregoing compounds, wherein the metal iscomplexed with the carbonyl groups of the diketone or keto-ester moiety.Such metals include copper (valence II), nickel, cobalt and the like.

In the above general formula I, Alk stands for a saturated aliphatichydrocarbon bridge containing from 3 to 10 carbon atoms. The alkylenebridge may be straight or branched. A preferred class of compounds arethose where Alk is straight chain alkylene of 3 to 10 carbon atoms, andif the Alk bridge is branched, it is preferred that it be symmetrical,that is with the branching at the same relative positions from eitherend of the bridge.

The alkylene bridge, Alk, is optionally interrupted by an oxygen atomseparated by at least two carbon atoms from the terminal bonds of Alk.The oxygen atom is preferably in the center of the alkylene bridge,equidistant from the terminal bonds of Alk.

The carbon chains of R and R' can be straight or branched.

When two or three monovalent substituents are present on the phenyl ringof Ar, they can be the same or different. In the event alkoxyalkoxy ispresent on the phenyl ring, it is preferred that the two oxygen atomstherein be separated by at least two carbon atoms. It is also preferredthat no more than one nitro or sulfo group be present on the phenylring.

The compounds of the invention are prepared according to the followingreaction sequence: ##STR2##

An alkali metal salt of a phenol (HOAr), M-O-Ar, where M is alkalimetal, preferably sodium or potassium, is interacted with an alkylenedihalide, X-Alk-X, where X is chlorine, bromine or iodine. The reactiontakes place with moderate heating, between about 50° and 100° C. in aninert solvent using equimolar quantities of reactants, or preferably astoichiometric excess of dihalide to minimize di-ether (Ar-O-Alk-O-Ar)formation. The di-ether that is formed is readily separated from thedesired mono-ether (II), because the former is a relatively high meltingsolid which separates readily from organic solvents while the mono-etherremains in solution.

In the final step, the mono-ether, X-Alk-O-Ar (II), is treated with thealkali metal enolate salt of a diketone or keto-ester of formulaRR'CH-M+, where R and R' have the meanings given hereinabove and M+ isan alkali metal cation, preferably lithium, sodium or potassium. Thereaction takes place in an inert solvent under anhydrous conditions atambient temperature or slightly above (25°-70° C.). If the mono-ether,X-Alk-O-Ar, is a chloride (X=Cl), it is preferably converted to the morereactive iodide (x=I) with an alkali metal iodide, prior to the finalalkylation step.

If it is desired to obtain compounds of formula I wherein Ar issubstituted by one to three hydroxy groups, the reaction between M-OArand X-Alk-X can be carried out with the corresponding compounds where Aris substituted by one to three benzyloxy or acyloxy groups. Thebenzyloxy or acyloxy group or groups can then be cleaved by catalytichydrogenolysis or hydrolysis, respectively.

It is not, however, essential that phenolic hydroxy groups be protectedin the form of ethers or esters at the final stage of the synthesisbecause the diketone or keto-ester reactant, RR'CH₂, is more acidic thanthe phenolic hydroxyl; hence the desired alkylation with the iodides orbromides (II, X is I or Br) will take place without affecting anyphenolic hydroxy groups which may be present.

Alternatively, in the final step, the alkali metal enolate salt can bereplaced by a heavy metal chelate of the diketone or keto-ester.Appropriate heavy metal chelates include the copper, nickel and cobaltchelates.

An alternative approach to the compounds of the invention is depicted inthe following reaction sequence: ##STR3## In this alternative approachan alkali metal enolate salt or a heavy metal chelate of a diketone orketo-ester (RR'CH₂) is interacted with an alkylene dihalide, X-Alk-X.The reaction takes place in an inert solvent under anhydrous conditionsat ambient temperature or slightly above (20°-70° C.), using equimolarquantities of reactants or a stoichiometric excess of dihalide. Theresulting haloalkyl diketone or keto-ester of formula III is theninteracted with an alkali metal salt of a phenol (HOAr), which reactiontakes place with moderate heating, between about 50° and 100° C. in aninert solvent under anhydrous conditions. In this approach, any freehydroxy groups present in Ar should be protected in the form of thebenzyl ether or an ester in order to prevent competing reactions withthe haloalkyl diketone.

The intermediates of formula III are novel compounds and within thepurview of the invention.

It is preferred to carry out the initial etherification step with adibromide (X-Alk-X where X is Br) because of the more ready availabilityof dibromides as compared to diiodides. The resulting bromide(X-Alk-O-Ar or RR'CH-Alk-X where X is Br) can be interacted directlywith the alkali metal enolate salt RR'CH-M+ or phenolate ArO-M+,respectively; or if desired converted to the corresponding iodide(X-Alk-O-Ar or RR'CH-Alk-X where X is I) which reacts somewhat moreeasily with the enolate or phenolate salt than does the bromide. Theconversion of II (X=Br) to II (X=I) or III (X=Br) to III (X=I) iseffected by heating the former with sodium or potassium iodide in aninert solvent, e.g. acetone.

The dihalides, X-Alk-X, where Alk is branched or oxygen interrupted arepreferably symmetrical, that is, the branching or hetero atom is in thesame relative position or positions with respect to the terminal halogenatoms, in order to avoid production of mixtures upon ether formation.

It is also possible to employ chlorobromoalkanes as the dihalidereactant, namely, Cl-Alk-Br. The use of such mixed dihalides has theadvantage that di-ether formation is eliminated or minimized, sincereaction occurs preferentially with the bromine atom, especially ifstoichiometric proportions of phenol and dihalide are used. Furthermore,it is possible by this variation in the procedure to obtain compoundswith unsymmetrically branched or oxygen interrupted alkylene bridgeswithout producing mixtures. The resulting chloroalkoxy aryl ether,Cl-Alk-O-Ar, or chloroalkyl diketone or keto-ester, Cl-Alk-CHR'R, mustthen be converted to the corresponding bromo or iodo compound before itwill react with the alkali metal phenolate or the alkali metal enolatesalt of a diketone or keto-ester, respectively. The chlorobromoalkanestarting materials can be prepared by reduction, e.g. with lithiumaluminum hydride, of a chloro-ester, Cl-Alk'-COOCH₃, to afford achloroalkanol, Cl-Alk-OH, followed by replacement of the hydroxy groupwith bromine, e.g. with phosphorus tribromide.

It is preferred to prepare compounds of formula I where the aryl groupis substituted by acyloxy by esterification of the corresponding hydroxycompounds with the appropriate acid halide or acid anhydride. Theacyloxy groups are derived from carboxylic acids having from one toabout ten carbon atoms, and having a molecular weight less than about200. Representative of the acyl radicals which can be present arelower-alkanoyl radicals, e.g., formly, acetyl, propionyl, butyryl,isobutyryl, caproyl, heptanoyl, octanoyl, trimethylacetyl, and the like;carboxy-lower-alkanoyl radicals, e.g., succinyl (β-carboxypropionyl);cycloalkyl-lower-alkanoyl radicals, e.g., β-cyclopentylpropionyl,β-cyclohexylpropionyl, and the like; monocarbocyclic aroyl radicals,e.g., benzoyl, p-toluyl, p-nitrobenzoyl, 3,4,5-trimethoxybenzoyl, andthe like; monocarbocyclic aryl-lower-alkanoyl or alkenoyl radicals, suchas phenylacetyl, β-phenylpropionyl, cinnamoyl, and the like; andmonocarbocyclic aryloxy-lower-alkanoyl radicals, such asp-chlorophenoxyacetyl, and the like; and amino-lower-alkanoyl, such asglycinyl, alaninyl, diethylaminopropionyl, piperidinopropionyl,pyrrolidinopropionyl, morpholinobutyryl, and the like. Whenmonocarbocyclic aryl groups are present in the ester moieties,monocarbocyclic aryl includes phenyl and phenyl substituted by from oneto three lower-alkyl, lower-alkoxy, halogen or nitro groups, whichsubstituents, if plural, can be the same or different. It is preferredthat no more than one nitro group be present.

It is preferred to prepare compounds of formula I where the aryl groupis substituted by carboxyl (COOH) by hydrolysis of the correspondingcompounds of formula I where the aryl group is substituted bycarboalkoxy. A sulfo group can be introduced into the aryl group of acompound of formula I by direct sulfonation with sulfuric acid.

It is preferred to prepare compounds of formula I where the aryl groupis substituted by dialkylaminoalkoxy by etherification of thecorresponding compounds of formula I where the aryl group is substitutedby hydroxy, effected by reacting an alkali metal salt of the latter witha dialkylaminoalkyl halide.

Biological evaluation of the compounds of the invention has shown thatthey possess antiviral activity. They have been found to be effectiveagainst one or more of a large variety of RNA and DNA viruses, includingMyxoviruses, e.g. influenza types A₀, A₁, A-2, B; Paramyxoviruses, e.g.parainfluenza types 1, 2, 3, and mumps virus; Picornaviruses, e.g. humanrhinoviruses, Coxsackie viruses types A, B, ECHO viruses, equinerhinoviruses; Reoviruses, types 1, 2, 3; Arboviruses, e.g. equineencephalomyelitis (Eastern, Western and Venezuelan), Semliki Forestvirus; miscellaneous RNA viruses, e.g. measles, distemper, respiratorysyncytial, rubella, vesicular stomatitis, hepatitis; Herpes viruses,e.g. HSV type I, II, herpesvirus simiae, herpesvirus varicellae,infectious bovine rhinotracheitis, cytomegalovirus, Marek's diseasevirus, Epstein-Barr virus; Poxviruses, e.g. variola, vaccinia;leukemogenic viruses. Both in vitro and in vivo antiviral activity havebeen found in the compounds of the invention. The in vitro testing ofthe compounds showed that they had minimal growth inhibitoryconcentrations (mic) ranging from about 0.3 to about 50 micrograms permilliliter. The mic values were determined by standard serial dilutionprocedures.

The structures of the compounds of the invention were established by themodes of synthesis, by elementary analysis, and by infrared and nuclearmagnetic resonance spectral determinations.

A still further aspect of the invention relates to compositions forcombatting viruses which comprise an antivirally effective amount of atleast one compound of formula I in admixture with a suitable carrier ordiluent, and to the method of combatting viruses by contacting the locusof said viruses with said compositions.

The Antiviral compositions are formulated by preparing a dilute solutionor suspension in an organic or aqueous-organic medium, for example ethylalcohol, acetone, dimethylsulfoxide, and the like; and are applied tothe locus to be disinfected by conventional means such as spraying,swabbing or immersing. Alternatively, the compounds can be formulated asointments or creams by incorporating them in conventional ointment orcream bases, such as alkylpolyether alcohols, cetyl alcohol, stearylalcohol and the like; as jellies by incorporating them in conventionaljelly bases such as glycerin and tragacanth; or as aerosol sprays orfoams.

The following examples will further illustrate the invention.

EXAMPLE 1 (a) 7-(2-Chloro-4-methoxyphenoxy)heptyl bromide.

A solution of 6.9 g. (0.172 mole) sodium hydroxide pellets in 160 ml.absolute ethanol was prepared with stirring at room temperature and asolution of 25 g. (0.158 mole) 2-chloro-4-methoxyphenol in 25 ml.absolute ethanol was added in a fine stream. The solution was stirred atroom temperature for 15 minutes, then warmed gently in a steam bath(40°-45° C.) for one-half hour. The reaction mixture was chilled toabout 5° C. in an ice bath and 123 g. (0.477 mole) 1,7-dibromoheptanewas added dropwise over a 30 minute period. The reaction mixture wasstirred and allowed to warm to room temperature, then stirred for 6hours at room temperature and boiled at reflux for fifteen hours.

The reaction mixture was evaporated in vacuo and the residue taken up inether, washed well with water and evaporated. Unreacted1,7-dibromoheptane was collected by distilling the residue at 10 mm. topot temperature 160°-170° C. The pot residue was distilled at 110°-115°C. (0.025 mm.) to give 38.5 g. of 7-(2-chloro-4-methoxyphenoxy)heptylbromide.

By replacing the 2-chloro-4-methoxyphenol in the foregoing preparationby a molar equivalent amount of phenol, p-chlorophenol, p-bromophenol,or 2,4,6-trichlorophenol, there can be obtained, respectively,7-phenoxyheptyl bromide, 7-(4-chlorophenoxy)heptyl bromide,7-(4-bromophenoxy)heptyl bromide, or 7-(2,4,6-trichlorophenoxy)heptylbromide.

By replacing the 1,7-dibromoheptane in the foregoing preparation by amolar equivalent amount of 1,3-dibromopropane there can be obtained3-(2-chloro-4-methoxyphenoxy)propyl bromide.

(b) 7-(2-Chloro-4-methoxyphenoxy)heptyl iodide.

A mixture of 38.5 g. (0.115 mole) of 7-(2-chloro-4-methoxyphenoxy)heptylbromide and 17.3 g. (0.115 mole) of sodium iodide in 450 ml. of acetonewas stirred at reflux for three hours. The reaction mixture was filteredhot, concentrated in vacuo, and the residue partitioned between waterand ether. The ether layer was dried over anhydrous sodium sulfate andconcentrated to give 44 g. of 7-(2-chloro-4-methoxyphenoxy)heptyliodide, used directly in the next reaction.

(c) Ethyl 2-acetyl-9-(2-chloro-4-methoxyphenoxy)nonanoate [I; Ar is2-Cl-4-CH₃ OC₆ H₃, Alk is (Ch₂)₇, R is CH₃ CO, R' is CH₃ CH₂ OCO].

Ethyl acetoacetate (11.9 g., 0.0915 mole) was added dropwise to astirred slurry of 0.656 g. (0.0830 mole) of lithium hydride in 75 ml. ofdimethylformamide. The latter mixture was stirred for one hour at90°-95° C., and there was then added in a fine stream 14.66 g. (0.383mole) of 7-(2-chloro-4-methoxyphenoxy)heptyl iodide in 30 ml. ofdimethylformamide. The reaction mixture was heated at 60°-70° C. for 42hours and then poured into ice and dilute hydrochloric acid. The mixturewas extracted with ether and the latter washed with water and saturatedsodium chloride solution, dried over anhydrous sodium sulfate andconcentrated. The residue (21 g.) was distilled, b.p. 197°-202° C.(0.015 mm. ), and redistilled, b.p. 205°-206° C. (0.03 mm.) to give 4 g.of ethyl 2-acetyl-9-(2-chloro-4-methoxyphenoxy)nonanoate.

Anal. Calcd. for C₂₀ H₂₉ ClO₅ : C, 62.41; H, 7.59; Cl, 9.21. Found: C,62.12; H, 7.61; Cl, 9.29.

By replacing the ethyl acetoacetate in the foregoing preparation by amolar equivalent amount of methyl acetoacetate or pentyl 3-oxooctanoatethere can be obtained, respectively, methyl2-acetyl-9-(2-chloro-4-methoxyphenoxy)nonanoate [I; Ar is 2-Cl-4-CH₃ OC₆H₃, Alk is (CH₂)₇, R is CH₃ CO, R' is CH₃ OCO], or pentyl2-hexanoyl-9-(2-chloro-4-methoxyphenoxy)nonanoate [I; Ar is 2-Cl-4-CH₃OC₆ H₃, Alk is (CH₂)₇, R is CH₃ (CH₂)₄ CO, R' is CH₃ (CH₂)₄ OCO].

By replacing the 7-(2-chloro-4-methoxyphenoxy)heptyl iodide in theforegoing preparation by a molar equivalent amount of 7-phenoxyheptyliodide, 7-(4-chlorophenoxy)heptyl iodide, 7-(4-bromophenoxy)heptyliodide, 7-(2,4,6-trichlorophenoxy)heptyl iodide, or3-(2-chloro-4-methoxyphenoxy)propyl iodide, prepared from thecorresponding bromides as described above in part (b), there can beobtained, respectively, ethyl 2-acetyl-9-phenoxynonanoate [I; Ar is C₆H₅, Alk is (CH₂)₇, R is CH₃ CO, R' is CH₃ CH₂ OCO]; ethyl2-acetyl-9-(4-chlorophenoxy)nonanoate [I; Ar is 4-ClC₆ H₄, Alk is(CH₂)₇, R is CH₃ CO, R' is CH₃ CH₂ OCO]; ethyl2-acetyl-9-(4-bromophenoxy)nonanoate [I; Ar is 4-BrC₆ H₄, Alk is (CH₂)₇,R is CH₃ CO, R' is CH₃ CH₂ OCO]; ethyl2-acetyl-9-(2,4,6-trichlorophenoxy)nonanoate [I; Ar is 2,4,6-Cl.sub. 3C₆ H₂, Alk is (CH₂)₇, R is CH₃ CO, R' is CH₃ CH₂ OCO]; or ethyl2-acetyl-5-(2-chloro-4-methoxyphenoxy)pentanoate [I; Ar is 2-Cl-4-CH₃-OC₆ H₃, Alk is (CH₂)₃, R is CH₃ CO, R' is CH₃ CH₂ OCO].

According to the procedures described hereinabove starting from theappropriate substitute phenol, alkylene dibromide and keto-ester, thefollowing compounds were prepared:

EXAMPLE 2: Ethyl 2-acetyl-11-(2-chloro-4-methoxyphenoxy)undecanoate [I;Ar is 2-Cl-4-CH₃ OC₆ H₃, Alk is (CH₂)₉, R is CH₃ CO, R' is CH₃ CH₂ OCO],golden yellow oil.

Anal. Calcd. for C₂₂ H₃₃ ClO₅ : C, 63.99; H, 8.06; Cl, 8.59. Found: C,64.55; H, 8.18; Cl, 8.91. 64.49 8.20

IR (oil film)ν.sub.(cm.spsb.-1.sub.) : 3070vw, 2995sh, 2985sh (arom.),2930s (--CH₃); 2850ms (--CH₂ --); 1738s, 1720s (C═O); 1595s; 1270ms;1210s; 1050ms+shldr.

NMR (20% CDCl₃ ; internal TMS) δ ppm (Ratio): 6.9(3) (arom.); 4.25 (2 of8) (O--CH₂ --CH₃); 3.98 (2 of 8) (--O--CH₂ --CH₂ --); 3.77 (3 of 8)(O--CH₃); 3.42 (1 of 8) (--CH--(C═O)₂); 2.22(3) (CH₃ --C═O).

EXAMPLE 3: Ethyl 2-acetyl-6-(2-chloro-4-methoxyphenoxy)hexanoate [I; Aris 2-Cl-4-CH₃ OC₆ H₃, Alk is (CH₂)₄, R is CH₃ CO, R' is CH₃ CH₂ OCO],b.p. 190°-192° C. (0.12 mm.).

Anal. Calcd. for C₁₇ H₂₃ ClO₅ : C, 59.56; H, 6.76; Cl, 10.34. Found: C,59.71; H, 6.85; Cl, 10.28.

EXAMPLE 4: Ethyl 2-acetyl-7-(2-chloro-4-methoxyphenoxy)heptanoate [I; Aris 2-Cl-4-CH₃ OC₆ H₃, Alk is (CH₂)₅, R is CH₃ CO, R' is CH₃ CH₂ OCO],b.p. 198°-199° C. (0.13 mm.).

Anal. Calcd. for C₁₈ H₂₅ ClO₅ : C, 60.59; H, 7.06; Cl, 9.94. Found: C,60.58; H, 6.98; Cl, 10.05.

EXAMPLE 5: Ethyl 2-acetyl-12-(2-chloro-4-methoxyphenoxy)-dodecanoate [I;Ar is 2-Cl-4-CH₃ OC₆ H₃, Alk is (CH₂)₁₀, R is CH₃ CO, R' is CH₃ CH₂OCO], golden yellow oil.

Anal. Calcd. for C₂₃ H₃₅ ClO₅ : C, 64.70; H, 8.26; Cl, 8.30. Found: C,64.99; H, 8.39; Cl, 8.50.

IR (oil film )ν.sub.(cm.spsb.-1.sub.) : 3060vw, 3000sh, 2985sh (arom.);2920s (CH₃); 2850ms (--CH₂ --); 1740ms, 1715 ms (C═O); 1495s; 1270ms,1210ms; 1050ms+shldr.

Example 6: Ethyl 2-acetyl-8-(2-chloro-4-methoxyphenoxy)octanoate [I: Aris 2-Cl-4-CH₃ OC₆ H₃, Alk is (CH₂)₆, R is CH₃ CO, R' is CH₃ CH₂ OCO],light yellow oil.

Anal. Calcd. for C₁₉ H₂₇ ClO₅ : C, 61.53; H, 7.34; Cl, 9.56. Found C,61.31; H, 7.46; Cl, 9.79.

IR (oil film )ν.sub.(cm.spsb.-1.sub.) : 3060vw, 3000sh, 2985sh (arom.);2940ms (CH₃); 2860m (--CH₂ --); 1740ms; 1720ms (C═O); 1495s; 1270ms;1210ms; 1050ms+shldr.

NMR (20% CDCl₃ ; internal TMS) δppm (Ratio); 6.68-70(3) (arom.); 4.16 (2of 8) (O--CH₂ --CH₃); 3.92 (2 of 8) (--O--CH₂ --CH₂ --); 3.70 (3 of 8)(--OCH₃); 3.38 (1 of 8) (--CH--(CO--₂); 2.16 (3) (--CO--CH₃); 1.22 (3 of16) (--CH₂ CH₃).

We claim:
 1. A compound of the formula ##STR4## wherein: Alk is alkylene of 3 to 10 carbon atoms;R is alkanoyl of 2 to 6 carbon atoms; R' is carboalkoxy of 2 to 6 carbon atoms; and Ar is phenyl or phenyl substituted by one to three substituents selected from the group consisting of alkoxy of 1 to 4 carbon atoms and halogen.
 2. Ethyl 2-acetyl-9-(2-chloro-4-methoxyphenoxy)nonanoate, according to claim
 1. 3. Ethyl 2-acetyl-11-(2-chloro-4-methoxyphenoxy)undecanoate, according to claim
 1. 4. Ethyl 2-acetyl-6-(2-chloro-4-methoxyphenoxy)hexanoate, according to claim
 1. 5. Ethyl 2-acetyl-7-(2-chloro-4-methoxyphenoxy)heptanoate, according to claim
 1. 6. Ethyl 2-acetyl-12-(2-chloro-4-methoxyphenoxy)dodecanoate, according to claim
 1. 7. Ethyl 2-acetyl-8-(2-chloro-4-methoxyphenoxy)octanoate, according to claim
 1. 8. A composition for combatting viruses which comprises an antivirally effective amount of at least one compound according to claim 1 in admixture with a suitable carrier or diluent.
 9. A method for combatting viruses which comprises contacting the locus of said viruses with a composition containing an antivirally effective amount of at least one compound according to claim 1 in admixture with a suitable carrier or diluent. 